Endometriosis, the presence of endometrial glands and stroma outside of the uterine cavity is one of the most common causes of chronic pelvic pain and infertility: it affects 1 in 10 women in the reproductive age group. This incidence increases up to 35-50% in patients with infertility. Multiple factors have been implicated in endometriosis-associated infertility including significant alterations in the molecular markers of endometrial receptivity in women and baboons. Based on our baboon model we propose that following the establishment of endometriosis, the eutopic endometrium undergoes a coordinated series of changes during the window of uterine receptivity that are aberrant compared to controls. These changes can be divided into three phases: The early response (1-3 months) is characterized by the upregulation of E2 regulated genes, followed by a transition into a progesterone (P4) resistant state (6-9 months) that results in the down regulation of P4 regulated genes (12-15 months). We propose that this aberrant alteration in gene and protein expression during the window of uterine receptivity is associated with the reduced fecundity in women and baboons with endometriosis. To test this hypothesis in Specific Aim 1 we will explore the possibility that in our baboon model the surgical removal of endometriotic lesions during the early (1 month) or transition (6 month) phases of the induced disease results in the reestablishment of a receptive endometrium and a reversal of the P4 resistance that develops as a result of this disease. In Specific Aim 2 we will determine if the increase in FOS, an E2 induced early response gene, results in epigenetic changes that reprogram the eutopic endometrium during the window of receptivity by inducing the expression of DMA 5-methylcytosine transferase (DNMT1), which causes hypermethylation and subsequent repression of endometrial HOXA10, progesterone receptor (PR) and other P4 regulated genes. In Specific Aim 3 the question whether the inflammatory peritoneal environment created by the presence of endometriotic lesions induces a uterine immunological environment that is not conducive to the establishment of pregnancy will be addressed. We will test the hypothesis that the decreased expression of CXCL12 and glycodelin in the eutopic endometrium results in the suppression of regulatory T cell migration and an increase in the number of cytotoxic T-cells which will impact on the survival of a fetal allograft. The proposed studies have direct clinical relevance since we can directly address the mechanisms of implantation failure as a consequence of endometriosis using a baboon model that recapitulates the human disease.